FY2019 saw the publication of a project which uncovered a role for CEBPD in promoting cancer stem cells. To improve cancer patient outcome significantly, we must understand the mechanisms regulating stem-like cancer cells, which have been implicated as a cause of metastasis and treatment resistance. The transcription factor CEBPD can exhibit pro- and anti-tumorigenic activities, but the mechanisms underlying the complexity of its functions are poorly understood. We identified a role for breast cancer cell intrinsic CEBPD in promoting cellular phenotypes that have been associated with cancer stem cells (CSC). While CEBPD expression is not abundant in most metastatic breast cancers, our data support a pro-tumorigenic role of CEBPD when expressed in subsets of tumor cells and/or through transient activation by the tumor microenvironment or loss of substrate adhesion. Using genetic mouse models and human breast cancer cell lines, we show that deletion or depletion of CEBPD reduced expression of stem cell factors and stemnness markers, sphere formation and self-renewal, along with growth of tumors and established experimental metastases in vivo. CEBPD is also known as a mediator of the innate immune response, which is enhanced by hypoxia and interleukin-6 (IL-6) signaling, two conditions that also play important roles in cancer progression. Our mechanistic data reveal CEBPD as a link that engages two positive feed-back loops, in part by directly targeting the IL-6 receptor (IL6RA) gene, and, thus, amplifying IL-6 and HIF-1 signaling. This study provides a molecular mechanism for the synergism of tumor micro-environmental conditions in cancer progression with potential implications for the targeting of cancer stem cells. To follow up on this work we are investigating methods to downregulate CEBPD in vivo. We are collaborating with Dr. Shapiro to develop nanoparticle delivery of siRNA to established tumors and metastases in mice. In addition, we have made major strides in characterizing a function for CEBPD in Inflammatory Breast Cancer. Inflammatory breast cancer (IBC) is an extremely aggressive subtype of breast cancer (BC; classified by NIH-GARD as Rare Disease) with pronounced racial and socioeconomic disparities. IBC is often at late stage when diagnosed and there is no disease-specific therapy. Among the unique features of IBC are high expression of E-cadherin, formation of E-cadherin-mediated cancer cell clusters (emboli) within the lymphovascular space, and skin invasions. Whether the ability to form emboli contributes to distant metastasis is presently unknown. We found that CEBPD is expressed in a subset of IBC cancers and also within emboli structures un patients. We have used an in vitro model of emboli-formation to demonstrate that CEBPD specifically supports the stability of proteins that contribute to cell-cell adhesion within emboli. Our ongoing work addresses the molecular mechanism of this activity and their relevance in vivo through mouse models. Lastly, we have been studying the role of CEBPD in the endoplasmic reticulum stress. Cancer cells often experience endoplasmic reticulum (ER) stress due to activated oncogenes and microenvironmental conditions such as nutrient deprivation and hypoxia. Cells activate the unfolded protein response (UPR) mediated by ATF6, IRE1/XBP1s and PERK/ATF4 pathways to support adaption to stress, accompanied by activation of inflammatory signaling. The elevated UPR in cancer cells contributes to enhanced cell survival and therapy resistance. Therefore, it is important to understand the full complexity of cellular responses to ER stress. Using a panel of breast cancer cell lines, we found that CCAAT-enhancer binding protein delta (CEBPD) is rapidly induced in response to various chemical and physiological inducers of ER stress. Transcription factor, CEBPD is most known for its role in pro-inflammatory signaling pathways and research from our laboratory documents its dual functions in breast cancer by both attenuating or enhancing oncogenic pathways depending on context. Using pharmacological inhibitors and RNAi of specific UPR effectors, we found that PERK-mediated STAT3 activation induces CEBPD gene expression concurrent with the activation of the classical UPR effectors, XBP1s and ATF4, suggesting a potential role in stress adaptation. Examination of the global transcriptional prolife using RNAseq confirmed that CEBPD specifically supports pathways involved in ER stress adaptation, such as chaperone functions, UPR transcription factors, autophagy and cytokine signaling. While XBP1s and ATF4 are known to activate these pathways, this is the first report of a role for CEBPD in this process. Functional assays showed that knock down of CEBPD in cancer cells increased susceptibility to ER stress induced cell death, as determined by PARP cleavage, caspase activation, and cell survival. CEBPD deficient cells also displayed reduced LC3II accumulation, suggesting impaired autophagy induction in response to ER stress. Taken together, our data show that CEBPD is a novel proximal effector of the ER stress response in breast cancer cells. CEBPD confers a survival advantage to cancer cells and promotes adaptive and inflammatory responses during ER stress. These data also add a novel mechanism for the tumor promoting functions of CEBPD. We are currently examining UPR target gene expression in MMTV-Neu driven wildtype and CEBPD knockout murine mammary tumors. We will also test if targeting CEBPD might sensitize cancer cells to ER stress inducing chemotherapeutics.